Project Summary/Abstract Approximately every 40 seconds, there is an incident of heart attack (acute myocardial infarction, AMI). This injury causes necrosis of heart leading to cardiac arrhythmia and reduced cardiac contractility, rendering progression of heart failure (HF) in many patients within five years of initial AMI. Unfortunately, the human heart does not regenerate after injury, and there is no approved clinical treatment that facilitates cardiac repair. Moreover, no regenerative mammalian models are established to identify molecular targets for bona fide cardiac repair. This proposal will address these limitations by studying regenerate mammal with a non-regenerator simultaneously. Acomys (African Spiny mice) is a mammal closely related to Mus (laboratory mouse). Recently, independent groups have reported that Acomys are capable of regenerating injured tissue in multiple organs. Most importantly, after AMI, Acomys demonstrated significant cardiac protection, with a higher survival rate than mice. Our preliminary studies revealed that Acomys is capable of rescuing cardiac function after AMI. This proposal will further dissect the effect of these alternative injury responses seen in Acomys. Based on our preliminary results, I proposed to explore the alternative injury response seen in Acomys. I hypothesized that pro-regenerative cellular signals in Acomys heart after AMI stimulate adult cardiomyocyte proliferation and result in enhanced myocardium recovery and survival. I will test this hypothesis by implementing the following two aims. Aim 1 will investigate the extent of cardiac repair and the role of cardiomyocyte proliferation in Acomys after a heart attack with direct comparison to Mus. I will examine cardiomyocyte proliferation in both species after AMI. Scar size, functional recovery and angiogenesis will also be characterized. Aim 2 of this proposal will investigate the effect of macrophage-derived signals on Acomys cardiac repair. Since cellular cross-talk between cardiac cells are important in both cardiac homeostasis and post-injury repair, cardiomyocyte proliferation after AMI is likely controlled by both intrinsic and extrinsic signals. Macrophages infiltrate the injured heart in abundance early after AMI, and have been shown to influence cardiac repair. Our preliminary data suggest that macrophage polarization in Acomys is different with more anti-inflammatory macrophages compared to Mus. I hypothesized that Acomys macrophage release extracellular signals that are more pro-regenerative than Mus macrophages. To test my hypothesis, I will employ both in vivo and in vitro techniques to enrich macrophage secretome and examine its effect on Mus cardiac repair. This proposal will establish Acomys as a novel mammalian model for studying cardiac recovery after ischemic injury. I anticipate the outcome of this study to provide a blueprint for the future development of novel cardiac therapies for cardiac patients.